Self-antigens represent the most relevant and abundant antigens to which the host's immune system must be tolerant. Induction and maintenance of tolerance to self-antigens is mediated by several mechanisms that prevent inappropriate damage to normal tissues. One mechanism that has gained significant attention in recent years relates to the critical role that bone marrow-derived antigen-presenting cells (APCs) play in the induction of tolerance to self-antigens. This emerging role of APCs in immune tolerance has been recently extended into the field of tumor immunology with the demonstration -as described in detail in this application- that tumor antigen processing and presentation by host's APCs also represents the dominant mechanism mediating tolerance to tumor antigens ("cross-tolerance"). The requirement for bone marrow derived APCs in both the induction of antigen-specific T-cell tolerance as well as in priming effective T-cell antitumor responses, places APCs at the center of a critical decision leading to immune activation versus immune tolerance. Although emerging evidence points to the state of activation and/or differentiation of the APC as the central determinant of T-cell priming versus tolerance, the signaling and molecular mechanism(s) involved in this critical decision remain to be elucidated. Therefore, in this proposal we will utilize a well-characterized model of tumor-induced antigen-specific T-cell tolerance to evaluate the role of Signal Transducer and Activator of Transcription-3 (Stat3), c-kit and mevalonate signaling pathways in the decision -at the APC level- leading to either tolerance or priming of antigen-specific T-cells. In addition, we will explore whether cross-tolerance to tumor antigens can be either prevented and/or reverted by strategies that target these intracellular signaling pathways in APCs. [unreadable] [unreadable]